Type I interferons (IFNs) (IFN-I) are a family of cytokines that signal through a ubiquitously expressed heterodimeric receptor IFNAR (heterodimer of IFNAR1 and IFNAR2) resulting in antiviral, antiproliferative and immunomodulatory effects. In humans, type I IFN is composed of at least 12 IFN-α protein subtypes and 1 subtype each for IFN-β, IFN-ε, IFN-κ, and IFN-ω. IFN-I release occurs in response to both microbial and sterile ligands. Upon receptor binding, IFN-I initiates a signaling cascade through activation of JAK1 and TYK2 leading to the phosphorylation of several STAT family members including STATs 1-6. STAT1 and STAT2 activation leads to the formation of a complex with IFN-regulatory factor 9 (IRF9) and this complex, also known as the IFN-stimulated gene factor 3 (ISGF3) complex, binds to IFN-stimulated response elements (ISREs) in the nucleus resulting in the transcription of many interferon-stimulated genes (ISGs) including IRF7 and CXCL10 (IP-10) (Gonzalez-Navajas et al., Nature reviews. Immunology 12, 125 (February, 2012). IFN-I also modulates cellular function through other pathways including the v-crk sarcoma virus CT10 oncogene homolog (avian)-like (CRKL), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) (Hervas-Stubbs et al., Clinical cancer research: an official journal of the American Association for Cancer Research 17, 2619 (May 1, 2011)).
Several immune-mediated inflammatory diseases or autoimmune diseases, such as lupus, including Systemic Lupus Erythematosus (SLE) and cutaneous lupus erythematosus (CLE), type I diabetes, psoriasis, Sjögren's disease, systemic sclerosis, rheumatoid arthritis, immune thrombocytopenia (ITP), Aicardi-Goutieres syndrome (AGS), myositis, common variable immune deficiency (CVID) and autoimmune thyroid disease are associated at least in a sub-population of patients with overexpression of IFN-inducible gene transcripts commonly called the IFN signature present in whole blood and/or tissue, or with elevated IFN-I.
SLE is a chronic autoimmune or immune-mediated inflammatory disease in which the production of pathogenic autoantibodies and immune complexes result in tissue damage across multiple organ systems. The disease displays a broad range of symptoms with heterogeneous clinical presentation and may include systemic, cutaneous, renal, musculoskeletal, neurological and hematological manifestations. SLE varies greatly in severity and is chronic, remitting or relapsing with flares of activity cycling with periods of improvement or remission that may last weeks, months, or years. IFN-α is elevated in SLE patients and is believed to promote a loss of tolerance to self. IFN-α has been shown to contribute to sustained dendritic cell activation and thus antigen presentation, and suppression of Treg function contributing to SLE. IFN-α also induces BLyS expression, a target for the marketed SLE therapeutic BENLYSTA™. A number of polymorphisms associated with production or response to IFN-I have been identified and account for over half of confirmed polymorphisms associated with SLE (Ghodke-Puranik & Niewold, International journal of clinical rheumatology 8, doi:10.2217/ijr.13.58 (2013)). Antibodies neutralizing various IFN-α subtypes (pan-IFN-α antibodies) are being evaluated in clinical trials for SLE (see, for example, Int. Pat. Publ. No. WO02/066649, Int Pat. Publ. No. WO05/059106, Int. Pat. Publ. No. WO06/086586, Int. Pat. Publ. No. WO09/135861).
IFN-ω constitutes approximately 15% of the total IFN-I activity in human leukocyte IFN preparations produced after viral infection (Adolf, Virology 175, 410 (April, 1990). IFN-ω gene expression has been reported to be elevated in SLE patients (Han et al., Genes and immunity 4, 177 (April, 2003); Yao et al., Hum Genomics Proteomics 2009, (2009)), and the ability of IFN-ω to induce DC differentiation has been reported (Walker and Tough, European journal of immunology 36, 1827 (July, 2006)). The anti-IFN-α antibodies currently in clinical trials (sifalimumab (MEDI-545), rontalizumab and AGS-009) do not neutralize IFN-ω. Clinical trial data with these antibodies indicate partial reduction of the type I IFN signature in patients after treatment with anti-IFN-α antibodies (Merrill et al., Ann Rheum Dis 70:1905-1913, 2011; Yao et al., Arthritis Rheum 60:1785-1796, 2009), and Phase 2 trial data with rontalizumab (a pan-anti-IFN-α antibody) indicated improvement in signs and symptoms of SLE, flare rates, and steroid burden at week 24 in a pre-specified biomarker defined group of Interferon Signature Metric (ISM)-Low moderate to severely active lupus subjects. No efficacy was seen in patients having higher levels of IFN-inducible gene expression pre-defined as ISM-High (Kalunian et al., 2012 ACR/ARHP Annual Meeting; Abstract #2622, 2012).
In addition to anti-IFN antibodies, anti-IFNAR1 antibodies are being investigated for the treatment of lupus (Wang et al., 2013; Clinical Pharmacology & Therapeutics accepted article preview 14 Feb. 2013; doi: 10.1038/clpt.2013.35). IFNAR1 blockage is likely to abolish IFN signaling induced by all type I IFNs, including IFN-β. IFN-β may play a more critical role in antiviral defense, as specific deletion of the gene encoding IFN-β incurs substantial susceptibility to a host of viruses when compared to similarly exposed mice having functional IFN-β (Lazear et al., J Virol 85:7186-7194; Deonarain et al., J Virol 74(7): 3404-340, 2000; Deonarain et al., Circulation 110: 3540-3543, 2004; Gerlach, et al., J Virol 80: 3438-3444, 2006). Therefore, anti-IFNAR1 antibodies may increase the risk of side effects.
Current standard of care for SLE includes corticosteroids, antimalarial drugs, immunosuppressants or B cell modulators. These therapeutics may exhibit toxicity and other serious side effects, and may not be suitable for treatment of all lupus patients. Thus, there is a need for additional therapeutic treatments for lupus and other immune-mediated inflammatory or autoimmune diseases.